Summary The overarching goal of our Program Project Grant (PPG) is to understand the mechanisms of aging and longevity by using comparative biology approach. The four projects within the PPG are investigating mechanisms of longevity using a collection of 18 rodent species with lifespans ranging from 3 to 32 years and widely divergent susceptibility to age-related diseases. Here we would like to expand our research into Alzheimer?s disease (AD) related dementias by developing Octodon degus (degu) as a new research model for the studies of AD. Degu is a rat-sized social rodent native to Chile. Degus are relatively long-lived with the maximum-recorded lifespan of 14 years. Remarkably, after age of 3, degus develop AD pathology that closely resembles the human condition. Aged degus begin to show cognitive impairment, their brains accumulate amyloid beta (A?) and tau deposits and display neuroinflammation. Furthermore, degu A? is much closer in sequence, to the human protein, differing by only one amino acid, than A? of mouse or rat. As degus are social animals, they display behaviors that can be used to monitor the progression of cognitive decline. Building on our experience establishing colonies of naked mole rats at the University of Rochester we have successfully established breeding colonies of degu. Our goal is to establish degu as a model for AD research. As it is still unclear what factors are important for development and resolution of AD, we propose the following aims: (1) test the role of type 2 diabetes mellitus in the neurodegeneration phenotype seen in the animals. Importantly, AD pathology in degu seems to be linked to high glycemic diet, which provides a good model for development of AD in humans; (2) interrogate transcriptomics and proteomics of different cell types in specific brain areas of the animals to better understand the susceptibilities of these areas to neurodegeneration and to identify modifiable factors. Many AD drugs that showed promise in transgenic mouse models failed in human trials, suggesting that the mouse models do not replicate key aspects of AD pathogenesis. Transgenic mice express mutant versions of human proteins that promote local A? overproduction. However, the key processes and genes involved in sporadic AD are still unresolved. Importantly, unlike other disease models, in degus we can interrogate the role of whole organismic processes in the development of the disease. Degus will provide the research community with a natural model for sporadic AD that can be used to find efficient therapeutic targets, test interventions before they are applied to humans, and to identify early disease biomarkers. This novel model has the potential to have strong impact on the field.